The experiments described in this Proposal are aimed at understanding the development of the stereotyped connections between motor neurons and muscles that allow for coordinated movement. Previous work from the Henderson laboratory found that the GDNF controls the motor pool-specific expression of Ets family transcription factors and subsequent motor pool migration within the spinal cord and target innervation. Our preliminary observations indicate that expression of another Ets family member, Er81, becomes restricted to a subpopulation of facial motor neurons at a time when these cells are innervating their target muscles and segregating somatopically into subnuclei within the hindbrain facial nucleus. Critically, Er81 is required for the innervation of specific facial muscles by these dorsolateral motor neurons. The experiments outlined in this proposal seek to understand the role played by Er81 in establishing connectivity and somatotopy in the developing facial nucleus. Specific Aim 1 will determine the muscle targets of the Er81-expressing neurons, investigate neuronal migration events that may underlie facial motor somatotopy, and inform the proposed study with a comprehensive time course of facial nerve outgrowth and muscle innervation. Specific Aim 3 will analyze the role of Er81 in migration and target innervation by developing facial motor neurons through phenotypic analysis of Er81 mutant mice. A candidate screen for peripheral Er81-inducing factors will be complemented by the evaluation of Cadherin-7 as a candidate downstream effector of Er81 in facial neuromuscular development and connectivity. and through the identification of the functional effectors downstream of Er81. The results of these Aims will be a better understanding of connectivity in a clinically-relevant population of motor neurons, and a new genetic pathway for the extrinsic and intrinsic control of neuromuscular connectivity. PUBLIC HEALTH RELEVANCE: The experiments outlined here aim to understand the development of the nerves controlling the muscles of facial expression. It is precisely these nerves that are affected in congenital facial paralysis disorders such as Mobius syndrome, raising the possibility that our experiments will provide insight into the cause of this and related diseases.